Movatterモバイル変換

[0]ホーム
URL:

CN109069575A - universal cancer vaccine - Google Patents

universal cancer vaccineDownload PDF

Info

Publication number
CN109069575A
CN109069575ACN201780025266.3ACN201780025266ACN109069575ACN 109069575 ACN109069575 ACN 109069575ACN 201780025266 ACN201780025266 ACN 201780025266ACN 109069575 ACN109069575 ACN 109069575A
Authority
CN
China
Prior art keywords
seq
polypeptide
certain embodiments
change
human
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201780025266.3A
Other languages
Chinese (zh)
Inventor
毛里齐奥·扎内蒂
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by IndividualfiledCriticalIndividual
Publication of CN109069575ApublicationCriticalpatent/CN109069575A/en
Pendinglegal-statusCriticalCurrent

Links

Classifications

Landscapes

Abstract

Described herein are compositions of matter and methods for treating cancer. The compositions comprise altered human telomerase polypeptides containing T cell epitopes that have been altered to increase immunogenicity. The method comprises administering the polypeptide or a nucleic acid, such as DNA or RNA, encoding the polypeptide to an individual having or at risk of having cancer.

Description

Universal cancer vaccine
Cross reference
This application claims in 2 months 2016 Application U.S. Serial Nos 62/298,956 submitted for 23rd, April 8 in 2016The equity of U. S. application 62/320,440 and the U. S. application 62/341,771 submitted on May 26th, 2016 that day submits；InstituteThere are these U. S. applications to be incorporated into this in its entirety.
Background technique
Human telomerase reverse transcriptase (TERT) is the potential target of composing type self tumor antigen and immunotherapy for cancer.?Past, the immunotherapy test for TERT are not able to achieve the hope using TERT as immunotherapeutic targets.For example, usingTERT is as in 25 clinical researches of antigen induction anti-tumor immune response, and only 2 researches show that objective clinical soundIt answers, even so, overall response rate is also below 20%.
Reverse transcriptase of telomere (TERT) is the component of Telomerase, and Telomerase is by its own RNA template (TERC)Reverse transcription come synthesize telomeric dna series connection 5'-TTAGGG-3' extracellular nucleotides repetitive sequence distinct cell enzyme.Telomerase and endThe discovery that the telomeric dna that granzyme mediates extends solves the problems, such as end duplication, the i.e. support mechanism of telomeric dna and end protectionProblem.People TERT is a kind of autoantigen, is made of about 1130 amino acid.In the mankind, pass through standard telomere repeat sequenceAmplification scheme (TRAP) measures, and telomerase activation detects in the tumour of the different tissues type more than 85%, but justOften it is not detected in tissue.
Tolerance is the developing main determining factor of individual immunity response, and exploitation is for autoantigen such as endThe major obstacle of the immunotherapy of granzyme.In ontogenetic process, by eliminating the T cell precursor of high-affinity and retaining lowThe T cell precursor of affinity, tolerance have moulded group library (repertoire).If antigen presenting cell is lacking costimulation pointT cell is activated in the case where sub (signal 2), tumour growth can also promote peripheral tolerance.Further, since aging and exhaustion, orPerson remolds cancer cell immunogenicity by immunoediting, and certain T cell specificity may lose as time go on.
The cellular response of B and T cell to antigen mainly determine as present on individual cells surface by human leucocyte antigen (HLA) (HLA)It is fixed.Intracellular antigen (for example, virus protein, oneself protein matter) is usually processed by proteasome in the cell, generates 8-10The polypeptide of a amino acid.8 to 10- aggressiveness are loaded on MHC I class HLA hypotype A, B and C molecule, to be presented to cytotoxicityCD 8+T cell.Then, these cytotoxic T cells, which can recognize and destroy, carries the organism for expressing the protein (for example, diseasePoison) cell.Thousands of kinds of different HLA allele are distributed between A, B and C locus.These allele are grouped intoDifferent type is assigned therein as such as A2 or B44.Some types are more more common than other types, and A2 type is the most universal.
Summary of the invention
Telomerase has expression in many stages of tumor development, as shown in Figure 1.In addition, telomerase promoter mutation existsIt is visible in many different cancer types.See Fig. 2.Therefore, Telomerase is a kind of attractive therapy intervention target, the treatmentIntervention especially includes being inoculated with polypeptide as described herein.Alternatively, T cell can be in vitro by antigen presenting cell or be pierced in vivoSwash, the antigen presenting cell load has the t cell response epitope as derived from the human telomerase polypeptide of change described herein.Pass throughChange the t cell epitope of low-affinity as shown in Figure 3A to promote and the combination of specific HLA, it can be to avoid previously described toleranceProperty problem.Fig. 3 B explanation, this method be for polypeptide corresponding with SEQ ID NO:13 it is feasible, which is combiningReplacement mutation with arginine to tyrosine at the polypeptide p1 (572 positions of wild type Telomerase) of HLA-A2.
Referring to fig. 4 with Fig. 5 (two different non-limiting schematic diagrames of the human telomerase polypeptide of change), Telomerase hasSeveral potential HLA combination polypeptides (rectangle), these polypeptides can be changed (black squares), thus with much stronger than wild typeThe affinity of form is in conjunction with HLA.If T cell auxiliary epitope (diamond shape) is applied, for example, by the way that such epitope to be building up toIn the Telomerase of change, then the telomere enzyme polypeptide changed can induce CD8+T cell response.Since these peptides are initially inEtc. affinity in conjunction with various HLA allele, therefore be directed to their endogenous CD8+T cell group library is not yet resistant to.It appliesThese T cells not being resistant to will be activated and expand with the Telomerase of the change of the polypeptide with one or more changes, to leadCause the immune response of Expression of Telomerase (for example, cancer) cell.
Cancer is carried out as antigen this document describes the Telomerase that may be used in change or the telomere enzyme polypeptide of change to exempt fromThe composition and method of epidemic disease therapy.The composition is useful, because they destroy the tolerance to autoantigen Telomerase,Also as they can promote response in the different individual of HLA haplotype.In certain embodiments, the composition includesOne or more HLA combination polypeptides from human telomerase, the HLA combination polypeptide change from its naturally occurring sequence,To assign the immunogenicity of enhancing.These change polypeptides be usually it is subdominant, therefore, have the T cell of response still to themIt is not resistant to.In certain embodiments, the polypeptide is applied respectively or is applied as single biggish polypeptide.In certain implementationsIn scheme, the polypeptide and T assist epitope, the ligand such as Toll-like receptor (TLR) or NOD of adjuvant or congenital immunity activating moleculesSample receptor (NLR) is applied together.There is also described herein the nucleic acid of encoding telomerase and t helper cell polypeptide, including RNA.
In certain embodiments, this document describes a kind of polypeptides, and it includes SEQ ID NO:2, SEQ ID NO:3, SEQID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ IDNO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ IDNO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ IDNO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27 extremelyA few sequence.In certain embodiments, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ IDNO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ IDIt is NO:23, SEQ ID NO:24, SEQ ID NO:25, at least two in SEQ ID NO:26 or SEQ ID NO:27 differentSequence.In certain embodiments, the polypeptide includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ IDIt is NO:23, SEQ ID NO:24, SEQ ID NO:25, at least three in SEQ ID NO:26 or SEQ ID NO:27 differentSequence.In certain embodiments, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ IDIt is NO:23, SEQ ID NO:24, SEQ ID NO:25, at least five in SEQ ID NO:26 or SEQ ID NO:27 differentSequence.In certain embodiments, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ IDIt is NO:23, SEQ ID NO:24, SEQ ID NO:25, at least ten in SEQ ID NO:26 or SEQ ID NO:27 differentSequence.In certain embodiments, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ IDIt is NO:23, SEQ ID NO:24, SEQ ID NO:25, at least seven in SEQ ID NO:26 or SEQ ID NO:27 differentSequence, wherein each of described seven different sequences combine the difference for being selected from A1, A2, A3, A11, A24, B3, B7 and B44Human leucocyte antigen (HLA).In certain embodiments, which includes that non-human T cell assists epitope, and wherein the non-human T cell assistsEpitope incorporates more than a kind of people II class HLA type.In certain embodiments, T cell auxiliary epitope includes tetanus poisonElement.In certain embodiments, T cell auxiliary epitope is selected from SEQ ID NO:30 to SEQ ID NO:55 and combinations thereof.?In certain embodiments, which assists epitope as shown in SEQ ID NO:30.In certain embodiments, which includesThe total length of at least 20 amino acid.In certain embodiments, which includes the total length of at least 50 amino acid.At certainIn a little embodiments, which includes the total length of at least 100 amino acid.In certain embodiments, nucleic acid molecule encodingThe polypeptide.In certain embodiments, the compound of at least eight continuous amino acid comprising the polypeptide and antigen presenting cellCell surface human leucocyte antigen (HLA) combines.In certain embodiments, which is B cell.In certain embodiment partyIn case, which is dendritic cells.In certain embodiments, this document describes include the polypeptide and immunologic adjuvantComposition.In certain embodiments, this document describes the compositions comprising the polypeptide and Toll-like receptor ligand.CertainIn embodiment, this document describes the groups comprising the polypeptide and pharmaceutically acceptable medium, carrier, excipient or combinations thereofClose object.In certain embodiments, this document describes the composition for assisting epitope comprising the polypeptide and non-human T cell, wherein shouldNon-human T cell assists epitope to incorporate more than a kind of people II class HLA type.In certain embodiments, which assists epitope packetContaining tetanus toxoid.In certain embodiments, T cell auxiliary epitope is selected from SEQ ID NO:30 to SEQ ID NO:55And combinations thereof.In certain embodiments, which assists epitope as shown in SEQ ID NO:30.
In another embodiment, this document describes a kind of human telomerase polypeptides of change, with SEQ ID NO:1 instituteShow sequence have at least 90% identity, wherein the human telomerase polypeptide of the change include at least one be located at position R19,L22、R132、L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、Amino acid replacement at R811, L840, G847, T874, L940, K981, V997 or P1020.In certain embodiments, describedThe human telomerase polypeptide of change is identical as SEQ ID NO:1 at least 95%.In certain embodiments, people's telomere of the changeEnzyme polypeptide contain at least two positioned at position R19, L22, R132, L152, D444, K492, E555, L556, T564, R572,Ammonia at R577, D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020The displacement of base acid.In certain embodiments, the human telomerase polypeptide of the change include at least three be located at position R19, L22,R132、L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、Amino acid replacement at L840, G847, T874, L940, K981, V997 or P1020.In certain embodiments, the changeHuman telomerase polypeptide include at least five be located at position R19, L22, R132, L152, D444, K492, E555, L556, T564,R572, R577, D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020The amino acid replacement at place.In certain embodiments, the human telomerase polypeptide of the change includes at least ten positioned at positionR19、L22、R132、L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、Amino acid replacement at T765, R811, L840, G847, T874, L940, K981, V997 or P1020.In certain embodimentsIn, at least one amino acid replacement makes the polypeptide of the 8-10 amino acid as derived from the human telomerase polypeptide of the change to A, BOr the binding affinity of at least one human leucocyte antigen (HLA) of c-type improves at least twice.In certain embodiments, at least oneAmino acid replacement make the polypeptide of the 8-10 amino acid as derived from the human telomerase polypeptide of the change to A, B or c-type at leastA kind of at least five times of binding affinity raising of human leucocyte antigen (HLA).In certain embodiments, at least one amino acid replacementKeep the polypeptide of the 8-10 amino acid as derived from the human telomerase polypeptide of the change white at least one people of A, B or c-type thinThe binding affinity of extracellular antigen improves at least ten times.In certain embodiments, the human telomerase polypeptide of the change includes non-Human T-cell assists insertion of the epitope into the polypeptide sequence of the human telomerase of the change, wherein non-human T cell's supplementary tablePosition incorporates more than a kind of people II class HLA type.In certain embodiments, T cell auxiliary epitope includes tetanus toxoid.In certain embodiments, T cell auxiliary epitope is selected from SEQ ID NO:30 to SEQ ID NO:55 and combinations thereof.CertainIn embodiment, which assists epitope as shown in SEQ ID NO:30.In certain embodiments, nucleic acid molecule encoding instituteState the human telomerase polypeptide of change.In certain embodiments, at least eight of the human telomerase polypeptide comprising the change is continuousThe compound of amino acid is in conjunction with the cell surface human leucocyte antigen (HLA) of antigen presenting cell.In certain embodiments, this is anti-Original is B cell in delivery cell.In certain embodiments, which is dendritic cells.In certain embodiments,This document describes include the human telomerase polypeptide of the change and the composition of immunologic adjuvant.In certain embodiments, hereinDescribe the composition of the human telomerase polypeptide comprising the change and Toll-like receptor ligand.In certain embodiments, originallyText describes the human telomerase polypeptide comprising the change and pharmaceutically acceptable medium, carrier, excipient or combinations thereofComposition.In certain embodiments, this document describes include the human telomerase polypeptide of the change and non-human T cell's auxiliaryThe composition of epitope, wherein the non-human T cell assists epitope to incorporate more than a kind of people II class HLA type.In certain embodimentsIn, it includes tetanus toxoid which, which assists epitope,.In certain embodiments, T cell auxiliary epitope is selected from SEQ IDNO:30 to SEQ ID NO:55 and combinations thereof.In certain embodiments, which assists epitope such as SEQ ID NO:30 instituteShow.
In another embodiment, this document describes a kind of human telomerase polypeptides of change, with SEQ ID NO:28Or sequence shown in 29 has at least 90% identity, wherein the human telomerase polypeptide of the change and SEQ ID NO:1 are notTogether.In certain embodiments, the human telomerase polypeptide of the change is identical as SEQ ID NO:28 or 29 at least 95%.At certainIn a little embodiments, the human telomerase polypeptide of the change is identical as SEQ ID NO:28 or 29 at least 98%.In certain implementationsIn scheme, the human telomerase polypeptide of the change is identical as SEQ ID NO:28 or 29 at least 99%.In certain embodiments,The human telomerase polypeptide of the change is identical as SEQ ID NO:28 or 29 at least 100%.In certain embodiments, described to changeThe telomere enzyme polypeptide of change makes the polypeptide of the 8-10 amino acid as derived from the human telomerase polypeptide of the change to A, B or c-typeThe binding affinity of at least one human leucocyte antigen (HLA) improves at least twice.In certain embodiments, at least one described ammoniaBase acid, which changes, makes the polypeptide of the 8-10 amino acid as derived from the human telomerase polypeptide of the change at least the one of A, B or c-typeThe binding affinity of kind human leucocyte antigen (HLA) improves at least five times.In certain embodiments, at least one described amino acid changesChange keeps the polypeptide of the 8-10 amino acid as derived from the human telomerase polypeptide of the change white at least one people of A, B or c-typeThe binding affinity of cellular antigens improves at least ten times.In certain embodiments, the human telomerase polypeptide of the change includesNon-human T cell assists insertion of the epitope into the polypeptide sequence of the human telomerase of the change, wherein the non-human T cell assistsEpitope incorporates more than a kind of people II class HLA type.In certain embodiments, T cell auxiliary epitope is selected from SEQ ID NO:30 to SEQ ID NO:55 and combinations thereof.In certain embodiments, which assists epitope as shown in SEQ ID NO:30.In certain embodiments, the human telomerase polypeptide of change described in nucleic acid molecule encoding.In certain embodiments, comprising describedThe compound of at least eight continuous amino acid of the human telomerase polypeptide of change and the cell surface human leukocytes of antigen presenting cellAntigen binding.In certain embodiments, which is B cell.In certain embodiments, the antigen presentation is thinBorn of the same parents are dendritic cells.In certain embodiments, this document describes human telomerase polypeptides and immunologic adjuvant comprising the changeComposition.In certain embodiments, this document describes human telomerase polypeptides and Toll-like receptor comprising the change to matchThe composition of body.In certain embodiments, it can be connect this document describes the human telomerase polypeptide comprising the change and pharmaceuticallyThe composition of the medium received, carrier, excipient or combinations thereof.In certain embodiments, this document describes change comprising describedThe human telomerase polypeptide of change and non-human T cell assist the composition of epitope, wherein the non-human T cell assists epitope to incorporate more thanA kind of people II class HLA type.In certain embodiments, T cell auxiliary epitope includes tetanus toxoid.In certain implementationsIn scheme, which assists epitope to be selected from SEQ ID NO:30 to SEQ ID NO:55 and combinations thereof.In certain embodimentsIn, which assists epitope as shown in SEQ ID NO:30.
In certain embodiments, this document describes for treat suffer from cancer individual method, this method include toIndividual application with cancer includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ IDNO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ IDNO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ IDNO:24, SEQ ID NO:25, at least one sequence in SEQ ID NO:26 or SEQ ID NO:27 polypeptide.In certain realitiesIt applies in scheme, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ IDNO:24, SEQ ID NO:25, at least two different sequences in SEQ ID NO:26 or SEQ ID NO:27.In certain realitiesIt applies in scheme, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ IDNO:24, SEQ ID NO:25, at least three different sequences in SEQ ID NO:26 or SEQ ID NO:27.In certain realitiesIt applies in scheme, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ IDNO:24, SEQ ID NO:25, at least five different sequences in SEQ ID NO:26 or SEQ ID NO:27.In certain realitiesIt applies in scheme, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ IDNO:24, SEQ ID NO:25, at least ten different sequences in SEQ ID NO:26 or SEQ ID NO:27.In certain realitiesIt applies in scheme, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ IDNO:24, SEQ ID NO:25, at least seven different sequences in SEQ ID NO:26 or SEQ ID NO:27, wherein describedEach of seven different sequences combine the different human leucocyte antigen (HLA)s for being selected from A1, A2, A3, A11, A24, B3, B7 and B44.In certain embodiments, the polypeptide includes the non-human polypeptides containing T cell auxiliary epitope, wherein the non-human T cell is auxiliaryEpitope is helped to incorporate more than a kind of people II class HLA type.In certain embodiments, T cell auxiliary epitope is selected from SEQ IDNO:30 to SEQ ID NO:55 and combinations thereof.In certain embodiments, which assists epitope such as SEQ ID NO:30 instituteShow.In certain embodiments, the polypeptide includes the total length of at least 20 amino acid.In certain embodiments, describedPolypeptide includes the total length of at least 50 amino acid.In certain embodiments, the polypeptide includes at least 100 amino acidTotal length.In certain embodiments, the nucleic acid molecules of coding said polypeptide are applied.In certain embodiments, the methodIncluding applying compound, which includes the polypeptide in conjunction with the cell surface human leucocyte antigen (HLA) of antigen presenting cellAt least eight continuous amino acid.In certain embodiments, which is B cell.In certain embodiments,The antigen presenting cell is dendritic cells.In certain embodiments, this method further includes application immunologic adjuvant.In certain implementationsIn scheme, this method further includes application Toll-like receptor ligand.In certain embodiments, this method further includes applying pharmaceuticallyAcceptable medium, carrier, excipient or combinations thereof.In certain embodiments, the cancer is hematology origin.?In certain embodiments, individual in need has Telomerase positive cancer.In certain embodiments, which is selected from bladderCancer, liver cancer, glioblastoma, melanoma, prostate cancer, thymic carcinoma, thyroid cancer and kidney.In certain embodiments,The method also includes application, non-human T cell assists epitope.In certain embodiments, T cell auxiliary epitope is selected from SEQID NO:30 to SEQ ID NO:55 and combinations thereof.In certain embodiments, which assists epitope such as SEQ ID NO:30It is shown.
In certain embodiments, the method for the individual this document describes a kind for the treatment of with cancer comprising to suffering fromThe individual application of cancer has the human telomerase polypeptide of at least change of 90% identity with sequence shown in SEQ ID NO:1,Described in change human telomerase polypeptide include at least one be located at position R19, L22, R132, L152, D444, K492, E555,L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、G847、T874、L940、K981、Amino acid replacement at V997 or P1020.In certain embodiments, the human telomerase polypeptide of the change and SEQ ID NO:1 at least 95% is identical.In certain embodiments, the human telomerase polypeptide of the change contain at least two positioned at position R19,L22、R132、L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、Amino acid replacement at R811, L840, G847, T874, L940, K981, V997 or P1020.In certain embodiments, describedThe human telomerase polypeptide of change include at least three be located at position R19, L22, R132, L152, D444, K492, E555, L556,T564, R572, R577, D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 orAmino acid replacement at P1020.In certain embodiments, the human telomerase polypeptide of the change includes at least five positioned at positionSet R19, L22, R132, L152, D444, K492, E555, L556, T564, R572, R577, D637, L675, E727, R742,Amino acid replacement at T765, R811, L840, G847, T874, L940, K981, V997 or P1020.In certain embodimentsIn, the human telomerase polypeptide of the change include at least ten be located at position R19, L22, R132, L152, D444, K492,E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、G847、T874、L940、Amino acid replacement at K981, V997 or P1020.In certain embodiments, at least one described amino acid replacement makes by instituteState at least one human leucocyte antigen (HLA) of the polypeptide to A, B or c-type of 8-10 amino acid derived from the human telomerase polypeptide of changeBinding affinity improve at least twice.In certain embodiments, at least one described amino acid replacement makes by the changeHuman telomerase polypeptide derived from 8-10 amino acid combination of the polypeptide at least one human leucocyte antigen (HLA) of A, B or c-typeAffinity improves at least five times.In certain embodiments, at least one described amino acid replacement makes the people end by the changeBinding affinity of the polypeptide of 8-10 amino acid derived from granzyme polypeptide at least one human leucocyte antigen (HLA) of A, B or c-typeIt improves at least ten times.In certain embodiments, the human telomerase polypeptide of the change includes that non-human T cell assists epitope to instituteThe insertion in the polypeptide sequence of the human telomerase of change is stated, wherein the non-human T cell assists epitope to incorporate more than a kind of people IIClass HLA type.In certain embodiments, the T cell auxiliary epitope be selected from SEQ ID NO:30 to SEQ ID NO:55 and itsCombination, wherein the non-human T cell assists epitope to incorporate more than a kind of people II class HLA type.In certain embodiments, the TCell assists epitope as shown in SEQ ID NO:30.In certain embodiments, the human telomerase of the application coding change is moreThe nucleic acid molecules of peptide.In certain embodiments, the method includes applying compound, which includes thin with antigen presentationThe cell surface human leucocyte antigen (HLA) of born of the same parents in conjunction with the polypeptide at least eight continuous amino acid.In certain embodiments, shouldAntigen presenting cell is B cell.In certain embodiments, which is dendritic cells.In certain embodimentsIn, this method further includes application immunologic adjuvant.In certain embodiments, this method further includes application Toll-like receptor ligand.In certain embodiments, this method further includes applying pharmaceutically acceptable medium, carrier, excipient or combinations thereof.?In certain embodiments, the cancer is hematology origin.In certain embodiments, individual in need has TelomerasePositive cancer.In certain embodiments, the cancer be selected from bladder cancer, liver cancer, glioblastoma, melanoma, prostate cancer,Thymic carcinoma, thyroid cancer and kidney.In certain embodiments, the method also includes application non-human T cells to assist epitope.?In certain embodiments, which assists epitope to be selected from SEQ ID NO:30 to SEQ ID NO:55 and combinations thereof.In certain realitiesIt applies in scheme, which assists epitope as shown in SEQ ID NO:30.
In certain embodiments, this document describes it is a kind for the treatment of with cancer individual method, this method include toIndividual with cancer applies the human telomerase polypeptide of change identical with SEQ ID NO:28 or 29 at least 90%, wherein describedThe human telomerase polypeptide of change is different from SEQ ID NO:1.In certain embodiments, the human telomerase polypeptide of the change withSEQ ID NO:28 or 29 at least 95% is identical.In certain embodiments, the human telomerase polypeptide Yu SEQ ID of the changeNO:28 or 29 at least 98% is identical.In certain embodiments, the human telomerase polypeptide Yu SEQ ID NO:28 of the change or29 at least 99% is identical.In certain embodiments, the human telomerase polypeptide Yu SEQ ID NO:28 or 29 of the change be at least100% is identical.In certain embodiments, the telomere enzyme polypeptide of the change makes derivative by the human telomerase polypeptide of the changeThe polypeptide of 8-10 amino acid at least twice is improved to the binding affinity of at least one human leucocyte antigen (HLA) of A, B or c-type.In certain embodiments, at least one described amino acid change makes the 8-10 as derived from the human telomerase polypeptide of the changeThe polypeptide of amino acid improves at least five times to the binding affinity of at least one human leucocyte antigen (HLA) of A, B or c-type.In certain realitiesIt applies in scheme, at least one described amino acid change makes as derived from the human telomerase polypeptide of the change 8-10 amino acidPolypeptide improves at least ten times the binding affinity of at least one human leucocyte antigen (HLA) of A, B or c-type.In certain embodimentsIn, the human telomerase polypeptide of the change includes human telomerase of the non-human polypeptides containing T cell auxiliary epitope to the changePolypeptide sequence in insertion, wherein the non-human T cell assist epitope incorporate more than a kind of people II class HLA type.CertainIn embodiment, which assists epitope to be selected from SEQ ID NO:30 to SEQ ID NO:55 and combinations thereof.In certain embodiment partyIn case, which assists epitope as shown in SEQ ID NO:30.In certain embodiments, application encodes the people of the changeThe nucleic acid molecules of telomere enzyme polypeptide.In certain embodiments, the method includes applying compound, which includes and resistsOriginal in delivery cell cell surface human leucocyte antigen (HLA) in conjunction with the polypeptide at least eight continuous amino acid.In certain implementationsIn scheme, which is B cell.In certain embodiments, which is dendritic cells.CertainIn embodiment, the method also includes applying immunologic adjuvant.In certain embodiments, this method further includes application Toll-likeReceptors ligand.In certain embodiments, this method further include apply pharmaceutically acceptable medium, carrier, excipient orA combination thereof.In certain embodiments, the cancer is hematology origin.In certain embodiments, individual in needWith Telomerase positive cancer.In certain embodiments, which is selected from bladder cancer, liver cancer, glioblastoma, melanocyteTumor, prostate cancer, thymic carcinoma, thyroid cancer and kidney.In certain embodiments, thin the method also includes applying inhuman TBorn of the same parents assist epitope.In certain embodiments, the T cell auxiliary epitope be selected from SEQ ID NO:30 to SEQ ID NO:55 and itsCombination.In certain embodiments, which assists epitope as shown in SEQ ID NO:30.
In certain embodiments, this document describes a kind of method for preparing treatment of cancer, this method includes mixed polypeptideAnd pharmaceutically acceptable medium, carrier, excipient or combinations thereof, the polypeptide include SEQ ID NO:2, SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27At least one sequence.In certain embodiments, the polypeptide includes SEQ ID NO:2, SEQ ID NO:3, SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ IDNO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ IDNO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27 extremelyFew two different sequences.In certain embodiments, the polypeptide includes SEQ ID NO:2, SEQ ID NO:3, SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ IDNO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ IDNO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27 extremelyFew three different sequences.In certain embodiments, the polypeptide includes SEQ ID NO:2, SEQ ID NO:3, SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ IDNO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ IDNO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27 extremelyFew five different sequences.In certain embodiments, the polypeptide includes SEQ ID NO:2, SEQ ID NO:3, SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ IDNO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ IDNO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27 extremelyFew ten different sequences.In certain embodiments, the polypeptide includes SEQ ID NO:2, SEQ ID NO:3, SEQ IDNO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ IDNO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ IDNO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27 extremelyFew seven different sequences, wherein each of described seven different sequences combine and are selected from A1, A2, A3, A11, A24, B3, B7The different human leucocyte antigen (HLA)s with B44's.In certain embodiments, the polypeptide includes that non-human T cell assists epitope, wherein instituteStating non-human T cell assists epitope to incorporate more than a kind of people II class HLA type.In certain embodiments, which assists epitopeSelected from SEQ ID NO:30 to SEQ ID NO:55 and combinations thereof.In certain embodiments, which assists epitope such as SEQShown in ID NO:30.In certain embodiments, the polypeptide includes the total length of at least 20 amino acid.In certain embodiment partyIn case, the polypeptide includes the total length of at least 50 amino acid.In certain embodiments, the polypeptide includes at least 100The total length of a amino acid.In certain embodiments, the method includes the nucleic acid molecules of polypeptide described in hybrid coding and medicinesAcceptable medium, carrier, excipient or combinations thereof on.In certain embodiments, this method includes that will include and resistOriginal in delivery cell cell surface human leucocyte antigen (HLA) in conjunction with the polypeptide at least eight continuous amino acid compound and medicineAcceptable medium, carrier, excipient or combinations thereof mix on.In certain embodiments, which is BCell.In certain embodiments, which is dendritic cells.In certain embodiments, the treatment is also wrappedInclude mixed immunity adjuvant.In certain embodiments, the treatment further includes mixing Toll-like receptor ligand.In certain embodiment partyIn case, the treatment further includes that mixing non-human T cell assists epitope.In certain embodiments, T cell auxiliary epitope is selected fromSEQ ID NO:30 to SEQ ID NO:55 and combinations thereof, wherein the non-human T cell assists epitope to incorporate more than a kind of people IIClass HLA type.In certain embodiments, which assists epitope as shown in SEQ ID NO:30.
In certain embodiments, this document describes a kind of method for preparing treatment of cancer, this method includes hybrid combiningObject and pharmaceutically acceptable medium, carrier, excipient or combinations thereof, the composition include to have with shown in SEQ ID NO:1Have a human telomerase polypeptide of at least change of 90% identity, the polypeptide include at least one be located at position R19, L22, R132,L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、Amino acid replacement at G847, T874, L940, K981, V997 or P1020.In certain embodiments, the people end of the changeGranzyme polypeptide is identical as SEQ ID NO:1 at least 95%.In certain embodiments, the human telomerase polypeptide of the change includesAt least two be located at position R19, L22, R132, L152, D444, K492, E555, L556, T564, R572, R577, D637,Amino acid replacement at L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020.In certain embodiments, the human telomerase polypeptide of the change include at least three be located at position R19, L22, R132, L152,D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、G847、Amino acid replacement at T874, L940, K981, V997 or P1020.In certain embodiments, the human telomerase of the changePolypeptide include at least five be located at position R19, L22, R132, L152, D444, K492, E555, L556, T564, R572, R577,Amino acid at D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020Displacement.In certain embodiments, the human telomerase polypeptide of the change include at least ten be located at position R19, L22, R132,L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、Amino acid replacement at G847, T874, L940, K981, V997 or P1020.In certain embodiments, at least one described ammoniaThe displacement of base acid makes the polypeptide of the 8-10 amino acid as derived from the human telomerase polypeptide of the change at least the one of A, B or c-typeThe binding affinity of kind human leucocyte antigen (HLA) improves at least twice.In certain embodiments, at least one described amino acid is setChanging keeps the polypeptide of the 8-10 amino acid as derived from the human telomerase polypeptide of the change white at least one people of A, B or c-typeThe binding affinity of cellular antigens improves at least five times.In certain embodiments, at least one described amino acid replacement make byThe polypeptide of 8-10 amino acid derived from the human telomerase polypeptide of the change is anti-to at least one human leukocytes of A, B or c-typeFormer binding affinity improves at least ten times.In certain embodiments, the human telomerase polypeptide of the change includes inhuman T thinBorn of the same parents assist insertion of the epitope into the polypeptide sequence of the human telomerase of the change, wherein the non-human T cell assists epitope knotClosing is more than a kind of people II class HLA type.In certain embodiments, T cell auxiliary epitope is selected from SEQ ID NO:30 to SEQID NO:55 and combinations thereof.In certain embodiments, which assists epitope as shown in SEQ ID NO:30.In certain realitiesIt applies in scheme, the method includes nucleic acid molecules of the human telomerase polypeptide of change described in hybrid coding and pharmaceutically acceptableMedium, carrier, excipient or combinations thereof.In certain embodiments, this method includes including and antigen presenting cellCell surface human leucocyte antigen (HLA) in conjunction with the polypeptide at least eight continuous amino acid compound with it is pharmaceutically acceptableMedium, carrier, excipient or combinations thereof mixing.In certain embodiments, which is B cell.CertainIn embodiment, which is dendritic cells.In certain embodiments, the treatment further includes mixed immunity assistantAgent.In certain embodiments, the treatment further includes mixing Toll-like receptor ligand.In certain embodiments, described to controlTreatment further includes that mixing non-human T cell assists epitope.In certain embodiments, T cell auxiliary epitope is selected from SEQ ID NO:30 to SEQ ID NO:55 and combinations thereof, wherein the non-human T cell assists epitope to incorporate more than a kind of people II class HLA type.In certain embodiments, which assists epitope as shown in SEQ ID NO:30.
In certain embodiments, this document describes a kind of method for preparing treatment of cancer, this method includes will be with SEQThe human telomerase polypeptide and pharmaceutically acceptable medium, carrier, figuration of the identical change of ID NO:28 or 29 at least 90%Agent or combinations thereof mixing, wherein the human telomerase polypeptide of the change is different from SEQ ID NO:1.In certain embodiments,The human telomerase polypeptide of the change is identical as SEQ ID NO:28 or 29 at least 95%.In certain embodiments, described to changeThe human telomerase polypeptide of change is identical as SEQ ID NO:28 or 29 at least 98%.In certain embodiments, the people of the changeTelomere enzyme polypeptide is identical as SEQ ID NO:28 or 29 at least 99%.In certain embodiments, the human telomerase of the changePolypeptide is identical as SEQ ID NO:28 or 29 at least 100%.In certain embodiments, the telomere enzyme polypeptide of the change make byThe polypeptide of 8-10 amino acid derived from the human telomerase polypeptide of the change is to v.At least one described amino acid change make byThe polypeptide of 8-10 amino acid derived from the human telomerase polypeptide of the change is anti-to at least one human leukocytes of A, B or c-typeFormer binding affinity improves at least five times.In certain embodiments, at least one described amino acid change makes to be changed by describedKnot of the polypeptide of 8-10 amino acid derived from the human telomerase polypeptide of change at least one human leucocyte antigen (HLA) of A, B or c-typeAffinity is closed to improve at least ten times.In certain embodiments, the human telomerase polypeptide of the change includes to assist containing T cellInsertion of the non-human polypeptides of epitope into the polypeptide sequence of the human telomerase of the change, wherein non-human T cell's supplementary tablePosition incorporates more than a kind of people II class HLA type.In certain embodiments, T cell auxiliary epitope is selected from SEQ ID NO:30To SEQ ID NO:55 and combinations thereof.In certain embodiments, which assists epitope as shown in SEQ ID NO:30.?In certain embodiments, the method includes the nucleic acid molecules of the human telomerase polypeptide of change described in hybrid coding and pharmaceutically may be usedThe medium of receiving, carrier, excipient or combinations thereof.In certain embodiments, this method includes that will include and antigen presentationThe cell surface human leucocyte antigen (HLA) of cell in conjunction with the polypeptide at least eight continuous amino acid compound and pharmaceutically may be usedThe medium of receiving, carrier, excipient or combinations thereof mixing.In certain embodiments, which is B cell.In certain embodiments, which is dendritic cells.In certain embodiments, the treatment further includes mixingImmunologic adjuvant.In certain embodiments, the treatment further includes mixing Toll-like receptor ligand.In certain embodiments,The treatment further includes that mixing non-human T cell assists epitope.In certain embodiments, T cell auxiliary epitope is selected from SEQID NO:30 to SEQ ID NO:55 and combinations thereof, wherein the non-human T cell assists epitope to incorporate more than a kind of people II class HLAType.In certain embodiments, which assists epitope as shown in SEQ ID NO:30.
In certain embodiments, this document describes a kind of methods for the treatment of cancer comprising uses coding SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQThe nucleic acid ex vivo transfection antigen presenting cell of any polypeptide in ID NO:27, SEQ ID NO:28 or SEQ ID NO:29.At certainIn a little embodiments, which is B cell.In certain embodiments, which is dendritic cells.
In certain embodiments, this document describes a kind of methods for the treatment of cancer comprising has used coding SEQID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ IDNO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ IDNO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ IDNO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ IDNO:26, SEQ ID NO:27, the antigen of the nucleic acid ex vivo transfection of any polypeptide is in SEQ ID NO:28 or SEQ ID NO:29Delivery cell.In certain embodiments, which is B cell.In certain embodiments, the antigen presenting cellIt is dendritic cells.In certain embodiments, application is more than 1 × 106A cell.It in certain embodiments, is intravenous administrationThe cell.
It is provided herein be comprising SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID in terms of someNO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ IDShown in any of NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26 or SEQ ID NO:27 at leastThe polypeptide of two sequences.In certain embodiments, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ IDNO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27 extremelyFew seven different sequences, wherein each of described seven different sequences combine and are selected from A1, A2, A3, A11, A24, B3, B7The different human leucocyte antigen (HLA)s with B44's.In certain embodiments, the polypeptide includes that non-human T cell assists epitope, wherein instituteStating non-human T cell assists epitope to incorporate more than a kind of people II class HLA type.In certain embodiments, the polypeptide includes extremelyThe total length of few 20 amino acid.In certain embodiments, the polypeptide is by polynucleotide encoding.In certain embodimentsIn, which includes ribonucleic acid (RNA).In certain embodiments, at least eight continuous amino acid of the polypeptide withThe cell surface human leucocyte antigen (HLA) of antigen presenting cell combines.In certain embodiments, the polypeptide also includes immune assistantAgent.In certain embodiments, the polypeptide also includes pharmaceutically acceptable medium, carrier or excipient.In certain realitiesIt applies in scheme, the polypeptide is used to treat the individual with cancer.
It is provided herein be a kind of human telomerase polypeptide of change in terms of some, with sequence shown in SEQ ID NO:1Arrange have at least 90% identity, wherein the human telomerase polypeptide of the change include at least one be located at position R19, L22,R132、L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、Amino acid replacement at L840, G847, T874, L940, K981, V997 or P1020.In certain embodiments, the changeHuman telomerase polypeptide include that non-human T cell assists insertion of the epitope into the polypeptide sequence of the human telomerase of the change,Described in non-human T cell assist epitope incorporate more than a kind of people II class HLA type.In certain embodiments, the changeHuman telomerase polypeptide is by polynucleotide encoding.In certain embodiments, the human telomerase polynucleotides of the change include coreRibosomal ribonucleic acid (RNA).In certain embodiments, at least eight continuous amino acid and antigen of the human telomerase polypeptide of the changeIt is combined in the cell surface human leucocyte antigen (HLA) of delivery cell.In certain embodiments, the human telomerase polypeptide of the change is alsoInclude immunologic adjuvant.In certain embodiments, the human telomerase polypeptide of the change also includes pharmaceutically acceptable mediumObject, carrier or excipient.In certain embodiments, the human telomerase polypeptide of the change is used to treat with cancerBody.
It is provided herein be a kind of human telomerase polypeptide of change in terms of some, appoint with SEQ ID NO:28 or 29Sequence shown in one has at least 90% identity, wherein the human telomerase polypeptide of the change is different from SEQ ID NO:1.In certain embodiments, the human telomerase polypeptide of the change includes that non-human T cell assists people end of the epitope to the changeInsertion in the polypeptide sequence of granzyme, wherein the non-human T cell assists epitope in conjunction with more than a kind of people II class HLA type.In certain embodiments, the human telomerase polypeptide of the change is by polynucleotide encoding.In certain embodiments, described to changeThe human telomerase polynucleotides of change include ribonucleic acid (RNA).In certain embodiments, the human telomerase polypeptide of the changeAt least eight continuous amino acid in conjunction with the cell surface human leucocyte antigen (HLA) of antigen presenting cell.In certain embodiments,The human telomerase polypeptide of the change also includes immunologic adjuvant.In certain embodiments, the human telomerase polypeptide of the changeIt also include pharmaceutically acceptable medium, carrier or excipient.In certain embodiments, the human telomerase of the change is morePeptide is used to treat the individual with cancer.
Detailed description of the invention
Fig. 1 is the schematic diagram for showing Telomerase and expressing in many different phases of cancer progression.
Fig. 2 is to show many different types of cancer schematic diagrames as caused by the mutation in telomerase promoter.
Fig. 3 A shows a diagram, illustrates that naturally combining the peptide of MHC I class HLA hypotype to have with low-affinity not yet lacksThe T cell group library lost or be resistant to.
Fig. 3 B shows the flow cytometry data of the tetramer staining of peripheral blood mononuclear cells.Should statistics indicate that, adoptThe immune CD8+T groups of cells library that can expand with the generation cross reaction of naturally occurring peptide carried out with the peptide of change.
Fig. 4 is the non-limiting schematic diagram of the telomere enzyme peptide changed, describes the epitope of multiple changes, and can combineThe integration non-human T cell of a variety of people MHC II class HLA types assists epitope.
Fig. 5 is second non-limiting schematic diagram of the telomere enzyme peptide changed, describes the epitope of multiple changes, Yi JinengThe integration non-human T cell of a variety of people MHC II class HLA types is enough combined to assist epitope.
Specific embodiment
In certain embodiments, include SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO this document describes one kind:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ IDNO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, in SEQ ID NO:26 or SEQ ID NO:27 extremelyThe polypeptide of a few sequence.
In certain embodiments, this document describes institutes in a kind of human telomerase polypeptide of change, with SEQ ID NO:1The sequence shown has at least 90% identity, wherein the human telomerase polypeptide of the change includes that at least one is located at positionR19、L22、R132、L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、Amino acid replacement at T765, R811, L840, G847, T874, L940, K981, V997 or P1020.
In certain embodiments, this document describes a kind of human telomerase polypeptide of change, with SEQ ID NO:28 orSequence shown in 29 has at least 90% identity, wherein the human telomerase polypeptide of the change is different from SEQ ID NO:1.
In certain embodiments, this document describes a kind of for treating the method for suffering from the individual of cancer, this method packetIt includes to the individual application with cancer and includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ IDNO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ IDNO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ IDNO:24, SEQ ID NO:25, at least one sequence in SEQ ID NO:26 or SEQ ID NO:27 polypeptide.
In certain embodiments, this document describes a kind of for treating the method for suffering from the individual of cancer comprising toIndividual application with cancer has the human telomerase of at least change of 90% identity more with sequence shown in SEQ ID NO:1Peptide, wherein the human telomerase polypeptide of the change include at least one be located at position R19, L22, R132, L152, D444, K492,E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、G847、T874、L940、Amino acid replacement at K981, V997 or P1020.
In certain embodiments, this document describes a kind of for treating the method for suffering from the individual of cancer, this method packetThe human telomerase polypeptide that change identical with SEQ ID NO:28 or 29 at least 90% is applied to the individual with cancer is included, whereinThe human telomerase polypeptide of the change is different from SEQ ID NO:1.
In certain embodiments, this document describes a kind of method for preparing treatment of cancer, this method includes that mixing includesSEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQThe polypeptide of at least one sequence in ID NO:26 or SEQ ID NO:27 and pharmaceutically acceptable medium, carrier, taxShape agent or combinations thereof.
In certain embodiments, this document describes a kind of method for preparing treatment of cancer, this method includes will be comprising changingThe composition of the human telomerase polypeptide of change is mixed with pharmaceutically acceptable medium, carrier, excipient or combinations thereof, described to changeSequence shown in the human telomerase polypeptide and SEQ ID NO:1 of change has at least 90% identity, is located at comprising at least onePosition R19, L22, R132, L152, D444, K492, E555, L556, T564, R572, R577, D637, L675, E727, R742,Amino acid replacement at T765, R811, L840, G847, T874, L940, K981, V997 or P1020.
In certain embodiments, this document describes a kind of method for preparing treatment of cancer, this method includes mixing and SEQThe human telomerase polypeptide of the identical change of ID NO:28 or 29 at least 90% and pharmaceutically acceptable medium, carrier, taxShape agent or combinations thereof, wherein the human telomerase polypeptide of the change is different from SEQ ID NO:1.
Certain definition
In the following description, in order to have a comprehensive understanding to various embodiments, certain details are elaborated.SoAnd it will be understood to those of skill in the art that embodiment provided by can implementing in the case where without these details.UnlessContext requires otherwise, otherwise in the whole instruction and subsequent claims, one word of " comprising " and its version,As "comprising" and " containing " should be explained in a manner of open, inclusiveness, that is, be interpreted as " including but not limited to ".Such as thisUsed in specification and appended book, singular "an", "one" and "the" include plural reference, unlessContext is expressly stated otherwise.It is also pointed out that one word of "or" is usually used with the meaning for including "and/or", unless context is anotherIt clearly states.In addition, headings provided herein is for convenience only, and the range of the claimed embodiment of non-explanationOr meaning.
As used herein, " about " word refers to the amount of about 10%, 5% or 1% near the amount.
" antigen " used herein is the molecule for referring to induce adaptive immune response in host organisms.
" epitope " used herein refers to be identified by immune system, especially by antibody, B-cell receptor or T cell receptorThe part of the antigen of identification, protein or polypeptide.
" immunologic adjuvant " used herein refer to it is any can be applied together with antigen, with enhancing exempt from response to the antigenThe substance of epidemic disease response.
" T cell auxiliary epitope " used herein is to refer to stimulation CD4+T cell secretory immune stimulating factor (for example,Cell factor, chemotactic factor (CF)), and in B cell, CD4+T cell and/or cytotoxicity CD8+Improve antigen in terms of t cell responseThe polypeptide of immunogenicity.The telomere enzyme polypeptide of change
In certain embodiments, this document describes composition of matter.SEQ ID NO:1 corresponds to wild type human TelomeraseThe amino acid sequence of protein.In certain embodiments as described herein, the composition is a kind of telomere enzyme polypeptide of change,The sequence shown in the SEQ ID NO:1 changes for it.In certain embodiments, the sequence shown in the SEQ ID NO:1 changesThe polypeptide of change changes in some way, thus the immunogenicity of enhancing one or more t cell epitopes as derived from it.?In certain embodiments, the telomere enzyme polypeptide of the change has been changed, to correspond to SEQ ID NO:28 or SEQ ID NO:Amino acid sequence shown in 29.In certain embodiments, the telomere enzyme polypeptide of the change has been changed, thus and SEQID NO:28 or SEQ ID NO:29 has 90% sequence identity.In certain embodiments, the Telomerase of the changePolypeptide has been changed, to have 95% sequence identity with SEQ ID NO:28 or SEQ ID NO:29.In certain implementationsIn scheme, the telomere enzyme polypeptide of the change has been changed, to have 97% with SEQ ID NO:28 or SEQ ID NO:29Sequence identity.In certain embodiments, the telomere enzyme polypeptide of the change has been changed, thus with SEQ ID NO:28Or SEQ ID NO:29 has 98% sequence identity.In certain embodiments, the telomere enzyme polypeptide of the change byChange, to have 99% sequence identity with SEQ ID NO:28 or SEQ ID NO:29.In certain embodiments, instituteThe telomere enzyme polypeptide for stating change has been changed, thus same with 100% sequence with SEQ ID NO:28 or SEQ ID NO:29One property.In certain embodiments, SEQ ID NO:28 or SEQ ID NO:29 includes to be inserted into SEQ ID NO:28 or SEQEpitope is assisted in the polypeptide sequence of ID NO:29 or in one or more T cells of N or C-terminal, they may be connect by flexibilityHead connection.In a further embodiment, the telomere enzyme polypeptide of the change may include the amino for not interfering t cell epitopeSour residue truncates or missing.
In certain embodiments, this document describes composition of matter.In certain embodiments, which isThe telomere enzyme polypeptide of the change of SEQ ID NO:1, wherein the change occur position R19, L22, R132, L152, D444,K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、G847、T874、At the position any one or more of L940, K981, V997, P1020 or any combination thereof.In certain embodiments, SEQThe change of ID NO:1 occur position R19, L22, R132, L152, D444, K492, E555, L556, T564, R572, R577,Any two in D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020At a or more position.In certain embodiments, SEQ ID NO:1 change occur position R19, L22, R132,L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、At three or more any positions in G847, T874, L940, K981, V997 or P1020.In certain embodiments,The change of SEQ ID NO:1 occur position R19, L22, R132, L152, D444, K492, E555, L556, T564, R572,Appointing in R577, D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020What four or more.In certain embodiments, SEQ ID NO:1 change occur position R19, L22, R132, L152,D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、G847、At any five or more positions in T874, L940, K981, V997 or P1020.In certain embodiments, SEQ IDThe change of NO:1 occur position R19, L22, R132, L152, D444, K492, E555, L556, T564, R572, R577,Any six in D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020At a or more position.In certain embodiments, SEQ ID NO:1 change occur position R19, L22, R132,L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、L840、At any seven or more positions in G847, T874, L940, K981, V997 or P1020.In certain embodiments,The change of SEQ ID NO:1 occur position R19, L22, R132, L152, D444, K492, E555, L556, T564, R572,Appointing in R577, D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020At what eight or more position.In certain embodiments, SEQ ID NO:1 change occur position R19, L22,R132、L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、R811、At any nine or more positions in L840, G847, T874, L940, K981, V997 or P1020.In certain embodimentsIn, the change of SEQ ID NO:1 occur position R19, L22, R132, L152, D444, K492, E555, L556, T564,R572, R577, D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 or P1020In any ten or more positions at.In certain embodiments, SEQ ID NO:1 change occur position R19,L22、R132、L152、D444、K492、E555、L556、T564、R572、R577、D637、L675、E727、R742、T765、At any 15 or more positions in R811, L840, G847, T874, L940, K981, V997 or P1020.CertainIn embodiment, the change of SEQ ID NO:1 occur position R19, L22, R132, L152, D444, K492, E555, L556,T564, R572, R577, D637, L675, E727, R742, T765, R811, L840, G847, T874, L940, K981, V997 orAt any 20 or more positions in P1020.In certain embodiments, the change of SEQ ID NO:1 occurs in placeSet R19, L22, R132, L152, D444, K492, E555, L556, T564, R572, R577, D637, L675, E727, R742,At any 25 or more positions in T765, R811, L840, G847, T874, L940, K981, V997 or P1020.In certain embodiments, the telomere enzyme polypeptide Yu SEQ ID NO:1 of the change keep 90% sequence identity.CertainIn embodiment, the telomere enzyme polypeptide and SEQ ID NO:1 of the change keep 95% sequence identity.In certain embodiment partyIn case, the telomere enzyme polypeptide and SEQ ID NO:1 of the change keep 97% sequence identity.In certain embodiments,The telomere enzyme polypeptide and SEQ ID NO:1 of the change keep 98% sequence identity.In certain embodiments, described to changeThe telomere enzyme polypeptide and SEQ ID NO:1 of change keep 99% sequence identity.In certain embodiments, the end of the changeGranzyme polypeptide includes the T cell auxiliary epitope being inserted into the polypeptide sequence.In certain embodiments, which assistsEpitope is inserted into N-terminal.In certain embodiments, which assists epitope to be inserted into C-terminal.In certain embodiments, by T cellIn any region for the telomere enzyme polypeptide that auxiliary epitope is inserted into the change, do not destroy as SEQ ID NO:2 to SEQ IDAny t cell epitope that NO:27 is listed.In certain embodiments, T cell auxiliary epitope is inserted into the telomere of the changeSomewhere in enzyme polypeptide between amino acid 1 40 and 440.In certain embodiments, T cell auxiliary epitope is inserted into instituteState the somewhere in the telomere enzyme polypeptide of change between amino acid 500 and 550.In certain embodiments, which assistsEpitope is inserted into the somewhere in the telomere enzyme polypeptide of the change between amino acid 770 and 810.In certain embodimentsIn, it includes the non-human polypeptides from virus, bacterium or helminth which, which assists epitope,.In certain embodiments, the TIt includes the sequence from tetanus toxoid protein matter that cell, which assists epitope,.In certain embodiments, which assists epitopeAs shown in SEQ ID NO:30.In certain embodiments, the composition includes that polypeptide and the Telomerase of the change is moreThe separated T cell of peptide assists epitope.In a further embodiment, the telomere enzyme polypeptide of the change, which may include, does not interfereThe amino acid residue of t cell epitope truncates or missing.
The HLA binding property of the telomere enzyme peptide of change
In certain embodiments, the amino acid change of SEQ ID NO:1 generates polypeptide, improves the knot to HLA moleculeClose affinity.In certain embodiments, the combination for changing the peptide and HLA molecule that make to change increases by twice.In certain embodiment partyIn case, the combination for changing the peptide and HLA molecule that make to change increases by five times.In certain embodiments, change make change peptide withThe combination of HLA molecule increases by ten times.In certain embodiments, which is A1, A2, A3, A11, A24, B7 and B44 classAny one or more of type.
In certain embodiments, this document describes composition of matter.In certain embodiments, which isA kind of polypeptide.In certain embodiments, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ IDNO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ IDNO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 are (for brevity, also referred to asSEQ ID NO:2 to SEQ ID NO:27) or any combination thereof shown in any one or more amino acid sequences.Table 1 showsThe HLA type of SEQ ID NO:2 to SEQ ID NO:27 and each self-bonding is gone out.In certain embodiments, which includesAny two shown in SEQ ID NO:2 to SEQ ID NO:27 or more amino acid sequence.In certain embodiments, shouldPolypeptide includes three or more any amino acid sequences shown in SEQ ID NO:2 to SEQ ID NO:27.In certain implementationsIn scheme, which includes any four or more amino acid sequence shown in SEQ ID NO:2 to SEQ ID NO:27.?In certain embodiments, which includes any five or more amino shown in SEQ ID NO:2 to SEQ ID NO:27Acid sequence.In certain embodiments, which includes any six or more shown in SEQ ID NO:2 to SEQ ID NO:27Multiple amino acid sequences.In certain embodiments, which includes any shown in SEQ ID NO:2 to SEQ ID NO:27Seven or more amino acid sequences.In certain embodiments, which includes SEQ ID NO:2 to SEQ ID NO:27 instituteAny eight or more the amino acid sequences shown.In certain embodiments, which includes SEQ ID NO:2 to SEQ IDAny nine or more amino acid sequences shown in NO:27.In certain embodiments, which includes SEQ ID NO:2To any ten or more amino acid sequences shown in SEQ ID NO:27.In certain embodiments, which includes SEQAny 15 or more amino acid sequences shown in ID NO:2 to SEQ ID NO:27.In certain embodiments, this is morePeptide includes any 20 or more amino acid sequences shown in SEQ ID NO:2 to SEQ ID NO:27.In certain implementationsIn scheme, which includes any 25 or more amino acid sequences shown in SEQ ID NO:2 to SEQ ID NO:27Column.In certain embodiments, which does not include SEQ ID NO:12.In certain embodiments, which does not include SEQID NO:13。
In certain embodiments, the polypeptide includes any two shown in SEQ ID NO:2 to SEQ ID NO:27Or more sequence, further connect between each polypeptide shown in SEQ ID NO:2 to SEQ ID NO:27 comprising amino acidHead.In certain embodiments, which is constructed by engineering for promoting the appropriate of cell in polypeptide processCutting.In certain embodiments, joint length is at least five amino acid.In certain embodiments, joint length is at least7 amino acid.In certain embodiments, joint length is at least ten amino acid.In certain embodiments, polypeptide lengthIt is at least 20 amino acid.In certain embodiments, polypeptide length is at least 30 amino acid.In certain embodiments,Polypeptide length is at least 40 amino acid.In certain embodiments, polypeptide length is at least 50 amino acid.In certain implementationsIn scheme, polypeptide length is at least 100 amino acid.In certain embodiments, polypeptide length is at least 150 amino acid.In certain embodiments, polypeptide length is at least 200 amino acid.In certain embodiments, polypeptide length is less than 500Amino acid.In certain embodiments, less than 400 amino acid of polypeptide length.In certain embodiments, polypeptide length is less than300 amino acid.
In certain embodiments, the polypeptide includes at least one shown in SEQ ID NO:2 to SEQ ID NO:27Amino acid sequence and T cell assist epitope.In certain embodiments, T cell auxiliary epitope is inserted into N-terminal.In certain realitiesIt applies in scheme, which assists epitope to be inserted into C-terminal.In certain embodiments, T cell auxiliary epitope is inserted into the polypeptideAny region, do not destroy another t cell epitope shown in SEQ ID NO:2 to SEQ ID NO:27.In certain implementationsIn scheme, it includes the non-human polypeptides from virus, bacterium or helminth which, which assists epitope,.In certain embodiments,T cell auxiliary epitope is listed in SEQ ID NO:30 to SEQ ID NO:55.In certain embodiments, the T cell is auxiliaryHelping epitope includes the sequence from tetanus toxoid protein matter.In certain embodiments, which assists epitope such as SEQShown in ID NO:30.In certain embodiments, the composition includes and separates polypeptide and the telomere enzyme polypeptide of the changeT cell assist epitope.
In certain embodiments, the polypeptide includes all known polypeptides for combining given HLA type.In certain implementationsIn scheme, which includes A1 conjugate SEQ ID NO:19 and SEQ ID NO:21.In certain embodiments, the polypeptide packetThe SEQ of conjugate containing A2 ID NO:5, SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:16, SEQID NO:20 and SEQ ID NO:25.In certain embodiments, which includes A3 conjugate SEQ ID NO:8, SEQ IDNO:11, SEQ ID NO:26 and SEQ ID NO:27.In certain embodiments, which includes A11 conjugate SEQ IDNO:8, SEQ ID NO:17 and SEQ ID NO:18.In certain embodiments, which includes A24 conjugate SEQ IDNO:14, SEQ ID NO:15 and SEQ ID NO:24.In certain embodiments, which includes B7 conjugate SEQ IDNO:4, SEQ ID NO:7 and SEQ ID NO:23.In certain embodiments, which includes B44 conjugate SEQ ID NO:2, SEQ ID NO:9 and SEQ ID NO:24.
In certain embodiments, the polypeptide includes at least seven different sequences, wherein described seven different sequencesEach of combine be selected from A1, A2, A3, A11, A24, B3, B7 and B44 different human leucocyte antigen (HLA)s.In certain embodiment partyIn case, which includes a kind of A1 conjugate selected from SEQ ID NO:19 and SEQ ID NO:21；Selected from SEQ ID NO:5,SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:16, SEQ ID NO:20 and SEQ ID NO:25A kind of A2 conjugate；One kind selected from SEQ ID NO:8, SEQ ID NO:11, SEQ ID NO:26 and SEQ ID NO:27A3 conjugate；A kind of A11 conjugate selected from SEQ ID NO:8, SEQ ID NO:17 and SEQ ID NO:18；Selected from SEQ IDA kind of A24 conjugate of NO:14, SEQ ID NO:15 and SEQ ID NO:24；Selected from SEQ ID NO:4, SEQ ID NO:7 andA kind of B7 conjugate of SEQ ID NO:23；And selected from SEQ ID NO:2, SEQ ID NO:9 and SEQ ID NO:24 oneKind B44 conjugate.
Nucleic acid
In certain embodiments, this document describes the cores for the telomere enzyme polypeptide for encoding polypeptide as described herein and changeAcid.In certain embodiments, which is plasmid.In certain embodiments, which is viral vectors.In certain implementationsIn scheme, which is adenovirus, slow virus, retrovirus, adeno-associated virus or vaccinia virus.In certain embodiment partyIn case, which includes RNA.In certain embodiments, nucleic acid encode SEQ ID NO:2 to any one of 55.?In certain embodiments, the nucleic acid encode any polypeptide embodiment as described herein.In certain embodiments, the nucleic acid is logicalConsensus promoter such as CMV promoter is crossed to express.In certain embodiments, the nucleic acid is by tissue-specific promoter come tableIt reaches.In certain embodiments, which is B cell specificity promoter.In certain embodiments, shouldTissue-specific promoter is immunoglobulin promoter/enhancer.
T cell assists epitope
In certain embodiments, any composition as described herein includes that T cell assists epitope.In certain embodimentsIn, any polypeptide as described herein includes that T cell assists epitope.In certain embodiments, any treatment side as described hereinMethod includes applying the telomere enzyme polypeptide of change together with T cell auxiliary epitope.In certain embodiments, which assistsEpitope is the conjugate mixed, and incorporates more than a kind of people MHC II class HLA type.In certain embodiments, the T cellAssisting epitope includes the non-human polypeptides from virus, bacterium or helminth.In certain embodiments, the T cell supplementary tablePosition includes artificial sequence.In certain embodiments, T cell auxiliary epitope includes the chimeric sequences from a variety of antigens.?In certain embodiments, T cell auxiliary epitope includes any SEQ ID listed in table 2.In certain embodiments, the TIt includes any one of SEQ ID NO:30 to SEQ ID NO:55 that cell, which assists epitope,.In certain embodiments, the T is thinIt includes the sequence from tetanus toxoid protein matter that born of the same parents, which assist epitope,.In certain embodiments, which assists epitope such asShown in SEQ ID NO:30.In certain embodiments, which assists epitope insertion end in a manner of destroying telomerase activationIn granzyme.
Antigen presenting cell
HLA molecule shape in certain embodiments as described herein, on telomere enzyme polypeptide and Antigen Presenting Cell surfaceAt compound.In certain embodiments, which includes SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ IDNO:11, S EQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQShown in ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or any combination thereofSEQ ID.In certain embodiments as described herein, pass through cell processing 8-10 derived from the telomere enzyme polypeptide of changeOne or more HLA molecule forming composites on a continuous amino acid and Antigen Presenting Cell surface.In certain embodimentsIn, after polypeptide is applied to individual, antigen presenting cell encounters telomere enzyme polypeptide in vivo.In certain embodiments, willThe polypeptide is added in vitro antigen presenting cell.In certain embodiments, ex vivo treatment antigen presenting cell, with activationIts antigen presentation capability.In certain embodiments, antigen presenting cell interferon gamma, granulocyte-macrophage colonyStimulating factor (GM-CSF), colony stimulating factor, TLR ligand, lipopolysaccharides, CpG ODN or any combination thereof are handled.In certain embodiments, which includes B cell.In certain embodiments, which includesDendritic cells.In certain embodiments, which includes macrophage.In certain embodiments, the antigenIt include artificial antigen in delivery cell in delivery cell.
Immunologic adjuvant
In certain embodiments, this document describes the combinations of the substance of telomere enzyme polypeptide and immunologic adjuvant comprising changeObject.In certain embodiments, this document describes the substances comprising SEQ ID NO:2 to any one of 29 He immunologic adjuvantComposition.In certain embodiments, which includes the adjuvant currently used for vaccine inoculation.In certain embodiments, shouldAdjuvant is inorganic salts.In certain embodiments, which includes alum salt.In certain embodiments, which includes phosphorusSour aluminium or aluminium hydroxide.In certain embodiments, which includes Quil A or saponin(e QS-21.In certain embodiments,The adjuvant includes N- acetylmuramyl-L alanyl-D- isoglutamine, also referred to as MDP.In certain embodiments, the assistantAgent includes IF, AMontanide, adjuvant 65 and Lipovant.In certain embodiments, which includes cell factor, such as dryDisturb plain γ or GM-CSF.
Toll-like receptor ligand
In certain embodiments, this document describes the telomere enzyme polypeptide comprising change and Toll-like receptor (TLR) ligand,The composition of matter of STING agonist or RIG-1 agonist.In certain embodiments, this document describes include SEQ IDThe composition of matter of NO:2 to any one of 29 and TLR ligand.In certain embodiments, the TLR ligand be LPS orCpG ODN.In certain embodiments, which passes through TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8Or any one of TLR9 activation signal conduction.In certain embodiments, which includes ring dinucleotides.In certain embodiments, which includes 5'ppp-dsRNA.
Pharmaceutically acceptable medium, carrier and excipient
In certain embodiments, this document describes telomere enzyme polypeptides and pharmaceutically acceptable medium comprising changeThe composition of matter of object, carrier or excipient.In certain embodiments, this document describes comprising in SEQ ID NO:2 to 29Any one and pharmaceutically acceptable medium, carrier or excipient composition of matter.In certain embodiments, shouldPharmaceutically acceptable medium, carrier or excipient include pH buffer or pH adjusting agent.In certain embodiments, the pHBuffer or pH adjusting agent include sodium bicarbonate, HEPES, MOPS, MEPES, phosphate buffer, Succinate Buffer, lemonLemon acid, ascorbic acid or any combination thereof.In certain embodiments, pharmaceutically acceptable medium, carrier or the figurationAgent includes salting liquid.In certain embodiments, which includes sodium chloride, potassium chloride, calcium chloride, hemin, benzylRope chloramines or any combination thereof.In certain embodiments, which includes carbonHydrate.In certain embodiments, which includes sucrose, dextrose, trehalose, lactose, cellulose, sorbSugar alcohol, galactolipin, glucan, xanthan gum or any combination thereof.In certain embodiments, the pharmaceutically acceptable mediumObject, carrier or excipient include amino acid or protein.In certain embodiments, the amino acid or protein include gelatin,Egg albumin, yeast extract, glutamate and albumin.In certain embodiments, the pharmaceutically acceptable medium,Carrier or excipient include emulsifier.In certain embodiments, which includes octylphenol ethoxylate (TritonX-100), polysorbate20, polysorbate80 (Tween 80), NaTDC or any combination thereof.In certain embodiment partyIn case, which includes chelating agent.In certain embodiments, the chelating agentInclude sodium ethylene diamine tetracetate (EDTA), EGTA or any combination thereof.In certain embodiments, the pharmaceutically acceptable matchmakerJie's object, carrier or excipient include liposome.In certain embodiments, which includes phosphatide, such as phosphatidyl choline.The liposome can be multilayer or single layer.
Administration route
In certain embodiments, polypeptide of the invention and nucleic acid can be applied in several ways.In certain embodiment partyIn case, the polypeptide is delivered by subcutaneous or intradermal injection.In certain embodiments, the polypeptide can pass through electroporationTo apply.In certain embodiments, the polypeptide is delivered by intra-tumoral injection.In certain embodiments, described morePeptide is delivered to spleen or lymph node by injection.In certain embodiments, the polypeptide is and intravenously applying and antigenIt is delivered in combination in the HLA of delivery cell.In certain embodiments, which is B cell.In certain embodiment partyIn case, which is dendritic cells.In certain embodiments, nucleic acid of the invention can be applied by transfectingWith.In certain embodiments, nucleic acid of the invention can be applied by electroporation.In certain embodiments, of the inventionNucleic acid can be applied by the ex vivo transfection of antigen presenting cell.In certain embodiments, which is B thinBorn of the same parents.In certain embodiments, which is dendritic cells.In certain embodiments, the telomere of the changeEnzyme polypeptide can be used together with Chimeric antigen receptor (CAR) T cell or NK cell.In certain embodiments, the CAR-T cellIt is specific for telomere enzyme peptide shown in SEQ ID NO:2 to SEQ ID NO:27.In certain embodiments, the CAR-NKCell is specific for telomere enzyme peptide shown in SE ID NO:2 to SEQ ID NO:27.
In certain embodiments, of the invention any with encoding from the individual separation antigen presenting cell with cancerThe nucleic acid ex vivo transfection of the telomere enzyme polypeptide of the change antigen presenting cell, is then applied to the individual.In certain embodimentsIn, which is transfected by lipofectin.In certain embodiments, which is worn by electricityHole transfects.In certain embodiments, which is transfected by viral vectors.In certain embodiments,The antigen presenting cell spontaneous transfection with the help of no specific transfection reagent.In certain embodiments, the antigen presentationCell includes B cell.In certain embodiments, which includes dendritic cells.In certain embodiments, shouldAntigen presenting cell includes macrophage.In certain embodiments, by 1x105To 5x106The antigen presenting cell of a transfectionIt is applied to individual.It in certain embodiments, will at least 1x105The antigen presenting cell of a transfection is applied to individual.CertainIt, will at least 1x10 in embodiment6The antigen presenting cell of a transfection is applied to individual.
Administration time table and method
In certain embodiments, this document describes the methods for using polypeptide or vaccination cancer of the invention.?In certain embodiments, it is primary that any polypeptide or nucleotide are applied to individual in need.In certain embodiments, will appointWhat polypeptide or nucleotide are applied to individual in need twice.In certain embodiments, any polypeptide or nucleotide are appliedThree times to individual in need.In certain embodiments, any polypeptide or nucleotide are applied to individual four times in needOr more time.In certain embodiments, just exempt from individual with a kind of polypeptide and with identical polypeptide booster immunization.In certain implementationsIn scheme, just exempt from individual with a kind of polypeptide and with different polypeptide booster immunizations.In certain embodiments, just exempted from nucleic acid aBody and with polypeptide booster immunization.In certain embodiments, dosage is given weekly once, once every two weeks, monthly or oftenYear is primary.In certain embodiments, spacing of doses is at least one month.In certain embodiments, spacing of doses is at leastTwo months.In certain embodiments, annual or booster every half a year is given to the individual for having reaction to treatment.
The preparation method for the treatment of of cancer
In certain embodiments, this document describes generate comprising SEQ ID NO:2 to SEQ ID NO:27 polypeptide withAnd the method for the telomere enzyme polypeptide changed.In certain embodiments, being includes any one prepared in SEQ ID NO:2 to 55The method of kind.Polypeptide of the invention can be generated by techniques known in the art.In certain embodiments, it has synthesized describedPolypeptide.In certain embodiments, the polypeptide is expressed in expression system appropriate, and uses such as filtering, precipitating, chromatographyThe standard technique purifying of method, centrifugation or any combination thereof.
Cancer
In certain embodiments, composition as described herein and method are used to treat the individual with cancer.CertainIn embodiment, which is in any stage of the cancer through histologic study proved.In certain embodiments, which has troubleThe risk of cancer.In certain embodiments, which is Telomerase positive.In certain embodiments, which isShow telomerase activation or the raised any cancer of levels of telomerase activity.Raised level of telomerase activity can be tested by TRAPOr the raising of Telomerase mRNA or protein level is shown.In certain embodiments, which is by telomerase promoterCaused by mutation in region.In certain embodiments, the cancer is related with the mutation in telomerase promoter subregion.At certainIn a little embodiments, which is solid tumor.In certain embodiments, which is hematological cancer.In certain implementationsIn scheme, which is the cancer of the brain.In certain embodiments, which is glioblastoma.In certain embodiments, shouldCancer is liver cancer.In certain embodiments, which is hepatocellular carcinoma.In certain embodiments, which is that uropoiesis is rawGrow the cancer of system.In certain embodiments, which is bladder cancer.In certain embodiments, shouldGenitourinary cancers are prostate cancers.In certain embodiments, which is kidney.In certain embodiments, shouldCancer is thyroid cancer.In certain embodiments, the cancer be prostate cancer, breast cancer, colon cancer, cancer of pancreas, melanoma,Lung cancer, gastric cancer or the cancer of the brain.In certain embodiments, which is leukemia, such as leukaemia or myeloma.In certain embodimentsIn, which is chronic myelogenous leukemia, acute myeloid leukaemia, chronic lymphocytic leukemia, the white blood of acute lymphoblasticDisease or Huppert's disease.
Embodiment
Following embodiment be it is illustrative, be not intended to limit invention as described herein.
Embodiment 1- is used to express the clinical test for the bladder cancer that the B cell of the plasmid transfection of the telomere enzyme polypeptide changed carries out
Clinical test is carried out to Telomerase Specific cancer such as bladder cancer/bladder transitional cell carcinoma patient.Curative effectTerminal is 24 months after treatment percentage survivals.Treatment method is the B cell group transfected with nucleic acid plasmid, the nucleic acid plasmidTelomerase of the coding corresponding to the change of SEQ ID NO:28 or 29.From every patient separating peripheral blood mononuclear cells, matter is usedGrain DNA spontaneous transfection in vitro, and cultivated 24 hours under cell type condition of culture appropriate.After the culture period, by certainlyBody shifts intravenous injection to the patient 1 × 105To 5 × 106A autologous B-cell.Patient interval receives to control three times in total for one monthIt treats.
Embodiment 2- is immunized melanoma patient using the telomere enzyme polypeptide changed
The 1mg telomere enzyme polypeptide changed subcutaneous or intradermal is applied to melanoma patient.The telomere enzyme polypeptide of the changeIt is prepared with immunologic adjuvant.Patient interval receives to treat three times in total for one month.
Embodiment 3- is immunized patients with hepatocellular carcinoma using Plasmid DNA combination electroporation
Using electroporation, in the matter for the telomere enzyme peptide that 10 different parts of patient intradermal application 100 micrograms coding changesGrain.It is total to co-administer 1 milligram.
Embodiment 4- passes through viral vector delivery booster
The viral vectors of booster is administered to people previously immune with nucleic acid or peptide.The coding of the viral vectors correspond toThe polypeptide or any other polypeptide disclosed herein of SEQ ID NO:28 or SEQ ID NO:29.Booster immunization is after initial immunityAt least one moon carries out.
It is aobvious and easy for those skilled in the art although the preferred embodiments of the invention have been illustrated and described hereinSee, these embodiments only provide in an illustrative manner.Those skilled in the art are existing without departing from the present inventionIt will be appreciated that a variety of variations, change and substitution.It should be understood that the various alternative solutions of embodiment of the present invention described hereinIt can be used for implementing the present invention.
SEQ ID NO:1 wild type human Telomerase
The human telomerase variant 1 that SEQ ID NO:28 changes
The human telomerase variant 2 that SEQ ID NO:29 changes

Claims (21)

CN201780025266.3A2016-02-232017-02-22universal cancer vaccinePendingCN109069575A (en)

Applications Claiming Priority (7)

Application NumberPriority DateFiling DateTitle
US201662298956P2016-02-232016-02-23
US62/298,9562016-02-23
US201662320440P2016-04-082016-04-08
US62/320,4402016-04-08
US201662341771P2016-05-262016-05-26
US62/341,7712016-05-26
PCT/US2017/018895WO2017147160A1 (en)2016-02-232017-02-22A universal cancer vaccine

Publications (1)

Publication NumberPublication Date
CN109069575Atrue CN109069575A (en)2018-12-21

Family

ID=59630504

Family Applications (1)

Application NumberTitlePriority DateFiling Date
CN201780025266.3APendingCN109069575A (en)2016-02-232017-02-22universal cancer vaccine

Country Status (3)

CountryLink
US (2)US9937247B2 (en)
CN (1)CN109069575A (en)
WO (1)WO2017147160A1 (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
CN109069575A (en)2016-02-232018-12-21毛里齐奥·扎内蒂universal cancer vaccine
US12433321B2 (en)2019-12-092025-10-07Nicoventures Trading LimitedOral composition with beet material
US12310959B2 (en)2019-12-092025-05-27Nicoventures Trading LimitedOral compositions with reduced water content
US11826462B2 (en)2019-12-092023-11-28Nicoventures Trading LimitedOral product with sustained flavor release
US11872231B2 (en)2019-12-092024-01-16Nicoventures Trading LimitedMoist oral product comprising an active ingredient
US11793230B2 (en)2019-12-092023-10-24Nicoventures Trading LimitedOral products with improved binding of active ingredients
US11617744B2 (en)2019-12-092023-04-04Nico Ventures Trading LimitedMoist oral compositions
US11969502B2 (en)2019-12-092024-04-30Nicoventures Trading LimitedOral products
US11883527B2 (en)*2019-12-092024-01-30Nicoventures Trading LimitedOral composition and method of manufacture
EP4358748A1 (en)2021-06-252024-05-01Nicoventures Trading LimitedOral products and method of manufacture

Citations (9)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
US5662907A (en)*1992-08-071997-09-02Cytel CorporationInduction of anti-tumor cytotoxic T lymphocytes in humans using synthetic peptide epitopes
US20020018806A1 (en)*2000-03-242002-02-14Babita AgrawalLipopeptide adjuvants
US20020102686A1 (en)*1998-03-312002-08-01Morin Gregg B.Inactive variants of the human telomerase catalytic subunit
CN1432411A (en)*2002-01-092003-07-30中国科学院上海细胞生物学研究所New use of gens mutant of human telomerase inverse transcriptase-like component
US20040086518A1 (en)*2000-02-152004-05-06Maurizio ZanettiUniversal vaccine and method for treating cancer employing telomerase reverse transcriptase
US20100166787A1 (en)*2006-07-282010-07-01David B WeinerVaccines and methods for using the same
US20110206736A1 (en)*2008-09-232011-08-25Thomas Jefferson UniversityCancer Vaccines Against Mucosal Antigens and Methods of Making and Using the Same
US20130129760A1 (en)*2010-02-162013-05-23Gustav GaudernackPolypeptides
CN104168912A (en)*2011-11-102014-11-26北京艾棣维欣生物技术有限公司Facilitator-DNA combination vaccine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
EP1257284A4 (en)2000-02-152005-12-21Univ California A UNIVERSAL VACCINE AND A METHOD FOR THE TREATMENT OF CANCER WITH TELOMERASE REVERSE TRANSCRIPTASE
US20090202499A1 (en)*2006-01-192009-08-13The Regents Of The University Of CaliforniaHuman Telomerase Reverse Transcriptase Peptides
WO2014127296A1 (en)*2013-02-142014-08-21Immunocellular Therapeutics, LtdCancer vaccines and vaccination methods
CN109069575A (en)2016-02-232018-12-21毛里齐奥·扎内蒂universal cancer vaccine

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
US5662907A (en)*1992-08-071997-09-02Cytel CorporationInduction of anti-tumor cytotoxic T lymphocytes in humans using synthetic peptide epitopes
US20020102686A1 (en)*1998-03-312002-08-01Morin Gregg B.Inactive variants of the human telomerase catalytic subunit
US20040086518A1 (en)*2000-02-152004-05-06Maurizio ZanettiUniversal vaccine and method for treating cancer employing telomerase reverse transcriptase
US20020018806A1 (en)*2000-03-242002-02-14Babita AgrawalLipopeptide adjuvants
CN1432411A (en)*2002-01-092003-07-30中国科学院上海细胞生物学研究所New use of gens mutant of human telomerase inverse transcriptase-like component
US20100166787A1 (en)*2006-07-282010-07-01David B WeinerVaccines and methods for using the same
US20110206736A1 (en)*2008-09-232011-08-25Thomas Jefferson UniversityCancer Vaccines Against Mucosal Antigens and Methods of Making and Using the Same
US20130129760A1 (en)*2010-02-162013-05-23Gustav GaudernackPolypeptides
CN104168912A (en)*2011-11-102014-11-26北京艾棣维欣生物技术有限公司Facilitator-DNA combination vaccine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
耿建等: "靶向人端粒酶逆转录酶T细胞表位肽的治疗性癌症疫苗研究进展", 《医学研究生学报》*

Also Published As

Publication numberPublication date
US11077177B2 (en)2021-08-03
US20170239336A1 (en)2017-08-24
WO2017147160A1 (en)2017-08-31
US9937247B2 (en)2018-04-10
US20180256691A1 (en)2018-09-13

Similar Documents

PublicationPublication DateTitle
CN109069575A (en)universal cancer vaccine
JP5416968B2 (en) Methods and compositions for eliciting a multivalent immune response against dominant and subdominant epitopes expressed on cancer cells and tumor stroma
US20230119334A1 (en)Antigen receptors and uses thereof
AU2006259221B2 (en)Multivalent entrain-and-amplify immunotherapeutics for carcinoma
US20210100885A1 (en)Cellular immunity inducing vaccine
US20240018274A1 (en)Enhanced Immunogenicity For GPI-anchored Antigens
Neukirch et al.Adenovirus based virus-like-vaccines targeting endogenous retroviruses can eliminate growing colorectal cancers in mice
EP3119422A2 (en)A medicament for use in a method of inducing or extending a cellular cytotoxic immune response
CA3211565A1 (en)Uses of amphiphiles in immune cell therapy and compositions therefor
Kramer et al.Functionalisation of Virus‐Like Particles Enhances Antitumour Immune Responses
CN112867502A (en)HERV-K derived antigens as consensus tumor antigens for use in anti-cancer vaccines
ES2357548T3 (en) PEPTIDE POLI-EPITOPE DERIVED FROM TIMIDYLATE SYNTHEASE THAT HAS IMMUNOLOGICAL AND ANTITUMORAL ACTIVITY.
KR20040104464A (en)Microorganisms as carriers of nucleotide sequences coding for cell antigens used for the treatment of tumors
US11725186B2 (en)Recombinant NK cells expressing co-stimulatory molecules
JP7585480B2 (en) Chimeric antigen containing the extracellular domain of PD-L1
CN118076378A (en) Anticancer vaccine composition comprising tumor-associated antigen-derived peptide and adjuvant consisting of lipopeptide and immunologically active substance and use thereof
US11382973B2 (en)Adjuvant composition and use thereof
CN108025044B (en)Immunogenic procalcitonin precursor peptides
KR20250043313A (en)A novel vaccine composition
Kinzler et al.Cancer vaccines
Arnaiz et al.256 Structural mimics of heat shock protein70 (Hsp70) associated peptides from breast tumour cells can prime T cells to respond to tumour antigens
Arsov et al.254 Frequencies of tetramer+ T cells specific for HPV16 E7 epitopes in the circulation of patients with squamous cell carcinoma of the oropharynx
Faivre-Bizouarne et al.255 MVA-MUC1-IL2 vaccine immunotherapy for advanced non-small cell lung cancer (NSCLC): interim phase II data
CN113318225A (en)Tumor immunopotentiator and its preparation method and application
HK40018015A (en)Antigen receptors and uses thereof

Legal Events

DateCodeTitleDescription
PB01Publication
PB01Publication
SE01Entry into force of request for substantive examination
SE01Entry into force of request for substantive examination
WD01Invention patent application deemed withdrawn after publication
WD01Invention patent application deemed withdrawn after publication

Application publication date:20181221
[8]ページ先頭
©2009-2025 Movatter.jp